Table 1 List of molecules directly or indirectly involved in process of tumor reversion (phenotype from tumor to normal) in human and mouse cancer cell lines/models

Translationally controlled tumor protein (TCTP)

TPT1

H1 parvovirus was used for preparing the revertants. TCTP was inhibited using anti-sense oligonucleotide or disruptive small RNA molecules

Breast (BT20, T47D, and MDA-MB-231) and leukemia (K562 and U937)

Reduction of TPT1/TCTP expression by anti-sense cDNA and siRNA in various breast cancer and leukemia cell lines was observed and the study concluded that TCTP gene downregulation is necessary for tumor reversion or to have a suppressed tumor phenotype.

Tuynder et al 2002 [15]

Seven in absentia homolog 1 (E3 ubiquitinprotein ligase)

SIAH1

H1 parvovirus was used for preparing the revertants.

Breast (BT20, T47D, and MDA-MB-231) and leukemia (K562 and U937)

SIAH1 transfectants observed to have suppressive tumor phenotype as compared with the control.

Tuynder et al 2002, [15]

Presenilin 1

PSEN1

The anti-sense complementary to PSEN1 was stable transfected in U937 cells.

Leukemic (K562 & U937)

TP53 and P21 genes endorsed PSEN1 expression. In an In vivo SCID mouse model, inhibition of PSEN1 led to suppression of tumor phenotype, retarded growth, and induction of apoptosis.

Roperch et al 1998, [20]

Signal transducer and activator of transcription 3

STAT3 (Transcription Factor)

Multiple myeloma cell line (RPMI8226) was infected with H1 parvovirus to make the revertant. The parental cells vs revertant cells compared using in vivo proteomics labeling technique SILAC followed by LCMS/MS analysis.

Multiple myeloma (RPMI8226)

The revertant cell line has a suppressed tumor characteristic compared to the parent cell line. Inhibition of STAT3 suppresses malignant phenotype, and induces apoptosis in vitro and in vivo state.

Ge et al 2010, [21]

K-rev-1 (RAP1A) GTPase

KREV1

Upon prolonged of PC3 cells with Azatyrosine, resistant clones were obtained and analyzed in both in vitro as well as in vivo conditions.

Prostate Cancer cell lines (TSU-Prl, DU-145, and PC-3)

The resistant PC3 clones showed very low number of colony forming ability, and complete loss of tumorigenicity observed in one clone. Further, KREV-1 expression was high in revertant as compared with parental cell line further confirmed induction of tumor reversion due to azatyrosine.

Benoit et al 1995, [16]

Rhoassociated protein kinase

ROCK

The inhibitors of ROCK as well as of mammalian target of rapamycin (mTOR) kinase inhibitors can substitute for all transcription factors (TFs) to be sufficient to reprogram breast cancer cells into progenitor cells.

Breast Cancer (MDA-MB-468, MDA-MB-231, and HCC2157)

In vitro and in vivo tumorigenesis tests have shown that induced fat-like cells lose proliferation and tumorigenicity. Reprogramming was possible by phenotypic changes by using ROCK–mTOR kinase inhibitors in breast cancer cell line that are induced progenitor-like cells (iPLs). These inhibitors prohibit locally the recurrence in mouse model.

Yuan et al 2018, [22]

Breast and ovarian cancer susceptibility protein 1

BRCA1

Targeted NGS was applied using circulating cell-free DNA (cfDNA) isolated from pre and postprogression plasma samples derived from high-grade ovarian carcinoma (HGOC) to profile BRCA mutations in rucaparib (PARP inhibitor)

Ovarian cancer

An important resistance mechanism to platinum-based chemotherapies and PARP inhibitors in BRCA1-mutant cancers was studied using cfDNA. This showed that the acquisition of BRCA1 reversion mutations capable of restoring the protein function.

Lin et al 2019 [17]

SET Domain Bifurcated 1 (Transcription regulatory protein)

SETDB1

The gene regulatory network (GRNs) analysis in previously datasets led to identification of identify core TFs (CDX2, ELF3, HNF4G, PPARG, and VDR) that control the cellular state.

Colorectal cancer cell lines (Caco2, HCT116, SW480, and SW620)

RNAseq analysis of single cell, showed upregulation of SETDB1 expression in stem like cancerous cells as compare with normal cells, and an elimination of SETDB1 in Caco2 cells shows KRT20+ population. This depletion led to changes of stem cancer cell phenotype into post-mitotic cells and led to restorage of normal morphology in colon cancer patient derived organoid.

Lee et al 2020, [23]

β1-integrin

TGB

Tyrosine kinase inhibitor (Tyrphostin AG 1478), Specific MAPK inhibit (PD98059), and I3K inhibitor (LY294002) were use to tre t the brea t ca er cell line.

Breast cancers (MCF7, HS578T, and MDA-MB-231)

An overexpression of E-cadherin gave rise to partial reversion, but when these transfected cells supplemented with beta1 integrin, PI3K or MAPK inhibitors, complete tumor reversion was achieved in MDA-MB-231 & MCF7.

Wang et al 2002, [24]

Homeobox D10 (Transcription factor)

HOXD10

Manipulation of MDA-MB-231 (breast cancer cell line) to restore the HOXD10 expression using retroviral gene expression system in a three-dimensional laminar pattern (3DlrBM).

Breast Cancer (MDA-MB-231)

Restorations of HOXD10 expression led to decreased expression of A3 integrin and reduced cellular proliferation and the cells were able to form acinar structures polarized in nature. Additionally, HOXD10 expression led to inhibition of tumorigenesis induced by MDA-MB-231 in mouse xenografts.

Carrio et al 2005, [25]

Matrix Metalloprotein ase9

MMP9

An MMP9 inhibitor GM6001 and another inhibitor of clinical grade (Marimastat) were tested for cellular behavior in 3D culture.

Breast Cancer (S1 and T4–2 cells of the HMT3522)

Both the agents were able to induce tumor reversion as compared with the control in these cell lines as evident with the morphological changes.

Beliveau et al 2010, [26] Coussens et al 2002, [27]

Mitogenactivated protein kinase.

MEK

Different isogenic variants of MCF10A were treated using MEKi inhibitor PD032590.

Transformed variants (isogenic cell lines in MCF10A, a normal human breast epithelial cell line) with different tumorigenic potential were used.

The MEKi inhibitor reverted the surfaceome changes in MCF10A cell line. Among isogenic variants of MCF10A, the most sensitive to MEKi were MEK^DD, BRAF^V600E, and EGFR^L858R

Leung et al 2020, [28]

YB-1 ( Transcription factor)

YBX1

Genome editing technique CRISPR/Cas9 was used to knockout.

Melanoma (MDA-MB-435), and MCF-7

Quashing of YBX1 led to inhibition of not only proliferation but also cell cycle arrest and apoptosis in melanoma as well as in breast cancer cells and generates inevitable cancer stem cell differentiation. This leads to reduce tumorigenic potential of CSCs in in vitro as well as in vivo conditions.

Yang et al 2019,[29]

Lipogenic enzyme fatty acid synthase (FASN)

FASN

Short hairpin RNA (shRNA) based inhibition of FASN

MCF10A progression series (MCF10A untransformed cells, MCF10AneoT and MCF10AT non-malignant cells, MCF10DCIS.com ductal carcinoma in situ cells and MCF10Ca1a, Ca1d and Ca1h malignant cell lines)

The Inhibition of FASN lead to suppression of lipogenesis in CA1d cells and also induced reversion of these cells into nonmalignant phenotype in breast cancer cells.

Gonzalez-Guerrico et al. 2016,[30]

Retinoic acid receptor α (RARα)

RARα

RARα agonist Am580 (4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl2-naphthyl)carboxamido]benzoic acid)

MMTV-Myc female mice fed on 0.3 mg/kg/day diet with RARα agonist

The RARα activation induce reexpression of CRBP1 which leads to reversion of the malignant phenotype.

Bosch et al 2012,[31]